Process for the preparation of stable radiodiagnostic products

ABSTRACT

Stable injection solutions of radiodiagnostic aids ready for use are obtained by addition to the organ- or tissue-specific carrier, before, during of after the labeling with the pertechnetate, of a compound of the formula:    &lt;IMAGE&gt;  (I)  in which R denotes hydrogen, and R&#39; denotes a sulpho- or a carboxymethyl group, or R and R&#39; each denote a sulpho- or a carboxymethyl group, or a water-soluble salt thereof, as stabilizer. These compounds do not alter the specific organ or tissue distribution of the carrier.

This application is a division of application Ser. No. 125,608, filedNov. 25, 1987.

The invention relates to stable products which are ready for use andlabeled with the radionuclide Tc-99m for use as radiodiagnostic aids, toa process for the preparation thereof, and to agents for carrying outthe process.

Skeletal scintigraphy with ^(99m) Tc-methylenediphosphonate (^(99m)Tc-MDP) is a method which is nowadays in-dispensable for the diagnosisof pathological processes in bone. Its place in nuclear medicine hasincreased continuously in importance in recent years. In fact, becauseof its sensitivity, this method is used in programmed time intervals inthe detection of disturbances of bone metabolism for the early diagnosisof bone metastases in the postoperative care of certain types of cancer.

Since several patients are referred each day to nuclear medicallaboratories for skeletal scintigraphy and, on the other hand, theoptimal interval between the administration of ^(99m) Tc-MDP or similarproducts and the scintigraphy is 2 to 3 hours, it would be an advantageto have available a radiopharmaceutical which can be labeled early inthe morning with a high level of radioactivity of ^(99m)Tc-pertechnetate and from which it is possible to take throughout theday as many single doses as patients referred for scintigraphy.

Furthermore, there have evolved, especially in the USA, Great Britainand Holland, what are called "radiopharmacies". Normally they do notthemselves carry out any nuclear medical investigations, but they dosupply on a daily basis, to smaller hospitals, nuclear medicallaboratories and private practices, single doses of products which areready for injection. It is important for these centers to have at handstable radiopharmaceuticals; they are then able to serve an extendedcircle of clients over a greater distance.

Now, as is known, injection solutions labeled with Tc-99m can be keptfor only a limited time, in contrast to the lyophilisates composed oforgan-specific carrier and reducing agent (for example tin(II) salt).Only a few hours after labeling, especially where the level of Tc-99mactivity is high, the presence of free pertechnetate can be detected inthe injection solution; this diminishes the quality of the products.This is because free pertechnetate accumulates in the stomach and in thethyroid, and in this way causes unnecessary exposure to radiation.Furthermore, it interferes with clear visualization of the target organsor tissues owing to a radiation background in the soft tissues.

The reversion of technetium ions to free pertechnetate derives from theoxidizing action of the residual oxygen which may be present in thesolution, but especially from that of various radiolytic products,especially of radicals and peroxides; the latter are continuously formedin aqueous solution as a consequence of radiolysis. In turn, thepresence of residual oxygen and even traces of heavy metal ionscatalyzes radiolysis.

Our investigations of eluates from the Tc-99m generator have shown thatthe content of peroxides in eluates, which are in practice usually leftto stand until used for the labeling of radiopharmaceuticals, increasesover the course of time. Table 1 shows that the rate of formation ofperoxides increases with the initial level of Tc-99m activity in theeluates (semi-quantitative peroxide determination using Merckoquant teststrips, Merck Cat. No. 10011). The detection limit of the method is 1ppm.

                  TABLE 1                                                         ______________________________________                                        Peroxide content (in ppm) of Tc-99m eluates                                   from Tc-99m generators                                                        Standing                                                                      time   57.2 GBq  41.5 GBq 32.9 GBq                                                                             27.9 GBq                                                                             12.2 GBq                              after  (1546     (1122    (889   (755   (330                                  elution                                                                              mCi)      mCi)     mCi)   mCi)   mCi)                                  ______________________________________                                        0-1  h     0         0      0      0      0                                   3    h     1         1      1      --     --                                  5    h     3         1-3    1-3    1-2    0                                   8    h     .sup. --.sup.1                                                                          3      3      --     --                                  26   h     --        --     --     0-1    0                                   48   h     --        --     --     0      0                                   ______________________________________                                         .sup.1 not determined                                                    

It has been proposed to stabilize the ^(99m) Tc-labeled injectionsolutions by, inter alia, the use of various chemical substances and, inparticular, of complexing agents. For example, cysteine [J. Nucl. Med.22 (1981), 645], hydroquinone (U.S. Pat. No. 4,229,427), gentisylalcohol (U.S. Pat. No. 4,232,000) and many other complex-formingcompounds (U.S. Pat. No. 4,027,005) have been investigated in thisrespect.

It has been particularly recommended to use, on the one hand, reducticacids, especially ascorbic acid, its salts and esters (German Pat. Nos.2,618,337, 2,619,382 and 2,660,424; U.S. Pat. Nos. 4,075,314, 4,440,738and 4,504,462; Canadian Pat. No. 1,114,291), or, on the other hand,hydroxy- and aminobenzoic acids, in particular 2,5-dihydroxybenzoic acidor gentistic acid, and their salts (U.S. Pat. Nos. 4,233,284, 4,451,451and 4,504,463; German Pat. No. 3,331,159; European Pat. No. 4,684; WO85/3231). The complexing agents ascorbic acid and gentisic acid, and4-aminobenzoic acid, have been used effectively in commercialradiopharmaceuticals.

However, the disadvantage associated with complexing agents is that theyform complexes not only with tin(II) and tin(IV) ions which are presentin excess but also with the ^(99m) technetium ions likewise. Thesecomplexes are soluble in water and hence are distributed throughout thebody and, in particular, in soft tissues, and in this way they generatea radiation background which diminishes the quality (sharpness) of thescintigraphic images. This is an undesired side effect which is commonto the complexing agents when used as stabilizers.

An additional factor is that the organ distribution and the excretion ofthe complexes formed from the ^(99m) technetium ions sometimes differfrom those of the organ- or tissue-specific Tc-99m radiopharmaceuticalswhich have to be prepared. For example, cysteine or ascorbic aciddiminishes the quality of the bone agent (pyrophosphate, diphosphonates)because Tc-99m-cysteine and Tc-99m-ascorbic acid undergo mainly renalexcretion. N-(4-Aminobenzoyl)glutamic acid andN-(4-aminobenzoyl)aspartic acid in high concentration as stabilizersincrease the renal excretion of the bone agent2,3-di-carboxypropane-1,1-diphosphonic acid.

It has now been found, unexpectedly, that compounds of the formula##STR2## in which R denotes hydrogen, and R' denotes a sulpho- orcarboxymethyl group, or R and R' each denote a sulpho- or acarboxymethyl group, and their water-soluble salts, exert an excellentstabilizing action, although they are not complexing agents, on ^(99m)Tc-pertechnetate and the injection solutions prepared therefrom. Thisfinding was all the more surprising because virtually all the compoundswhich have hitherto been proposed or used as stabilizers are complexingagents.

The above formula embraces specifically 2,5-dihydroxybenzenesulphonicacid, 2,5-dihydroxybenzene-1,4-disulphonic acid,2,5-dihydroxyphenylacetic acid and2,5-dihydroxy-4-carboxymethylphenylacetic acid. Particularly suitablewater-soluble salts are the alkali metal and ammonium salts; the sodiumsalts are preferred.

The fact that these compounds and their water-soluble salts do not formstable or water-soluble complexes, either with transition metals or withheavy metals, in the physiologically tolerated pH range of about 4 to 9is evident from the following experiment.

The compound to be tested is dissolved in water, and the solution isadjusted to a pH below 2 using dilute hydrochloric acid, and is mixedwith a solution of SnF₂ or SnCl₂.2H₂ O in 0.1N hydrochloric acid. Theresulting solution is completely clear; as is known, stable solutions oftin(II) ions are obtained only in strongly acid or strongly alkalinemedium (formation of stannite ions in the second case). The pH is thenincreased to a middling level by slow addition of dilute sodiumhydroxide solution. If the solution remains clear, the compound hasbound the tin(II) ions to form a complex; on the other hand, ifturbidity develops (basic tin salts, tin hydroxide) no complex has beenformed.

                  TABLE 2                                                         ______________________________________                                        pH and appearance of aqueous solutions of tin (II) salts                      Content in                                                                    10 ml of solution     pH      Appearance                                      ______________________________________                                        5    mg    SnCl.sub.2.2 H.sub.2 O                                                                            <2   clear                                                                   2 to 12                                                                             turbid                                                                  >12   clear                                     4    mg    SnF.sub.2                                                          50   mg    ascorbic acid      4.7   clear                                     5    mg    SnCl.sub.2.2 H.sub.2 O                                             100  mg    1,2-dihydroxybenzene                                                                             7.6   clear                                                (catechol)                                                         5    mg    SnCl.sub.2.2 H.sub.2 O                                             100  mg    1,2,3-trihydroxybenzene                                                                          6.0   clear                                                (pyrogallol)                                                       4    mg    SnF.sub.2                                                          50   mg    2,5-dihydroxybenzoic acid                                                                        6.5   clear                                                (gentisic acid)                                                    5    mg    SnCl.sub.2.2 H.sub.2 O                                             100  mg    1,2-dihydroxybenzene-3,5-                                                                        6.0   clear                                                disulphonic acid (Tiron)                                           5    mg    SnCl.sub.2.2 H.sub.2 O                                             100  mg    2,5-dihydroxybenzenesulphonic                                                                    3.0   turbid                                               acid                                                               4    mg    SnF.sub.2                                                          50   mg    2,5-dihydroxybenzene-1,4-                                                                        3.5   turbid                                               disulphonic acid                                                   5    mg    SnCl.sub.2.2 H.sub.2 O                                             100  mg    2,5-dihydroxyphenylacetic                                                                        2.6   turbid                                               acid                                                               5    mg    SnCl.sub.2.2 H.sub.2 O                                             100  mg    2,5-dihydroxy-4-carboxy-                                                                         4.3   turbid                                               methylphenylacetic acid                                            ______________________________________                                    

It is evident from Table 2 that with complexing agents such as ascorbicacid, gentisic acid etc. the tin(II) ions form stable complexes whichare soluble in weakly acid to weakly alkaline media.

Now the compounds of the formula (I) are readily soluble in water in thepH range from 2 to 9. Thus the turbidity found in this pH range can beexplained only by there being no complexes formed by these compoundswith the tin(II) ions; in this they contrast sharply with the customarystabilizers.

Nevertheless, addition of the said compounds in low concentration toTc-99m-radiodiagnostic aids stabilizes them against the oxidizing actionof the peroxides and free radicals which are formed over the course oftime. Even after labeling with high Tc-99m activity (at least 5.5 GBq,150 mCi) solutions of this type prove to be stable for several hours (atleast 4 hours).

This action is illustrated in Table 3 by the example of thebone-specific carrier methylenediphosphonic acid (MDP). 20 mg portionsof this compound are each dissolved in 1.0 ml of water and introducedinto ampuls; then tin(II) fluoride and sodium pertechnetate and, whereappropriate, a stabilizer in low concentration are added to the contentsof the ampul. The content of free ^(99m) Tc-pertechnetate is determinedafter 10 minutes and 5 and 8 hours, and is calculated as a % of theactivity used for labeling. The determination is carried out byhigh-voltage radioelectrophoresis (HVE) on Whatman paper 1 with acetatebuffer (0.04M; pH 6.5; 2,000 volt, 30 minutes) or by thin-layerradiochromatography (TLRC) on Whatman paper 31 ET with acetone as mobilephase.

                                      TABLE 3                                     __________________________________________________________________________    Stabilizing action of the compounds (I) on .sup.99m Tc-methylenediphosphon    ate                                                                            Contents of the ampul                                                                              % content of free pertechnetate                         (beside 20 mg MDP in                                                                       Activity used                                                                          Determination by HVE                                    1.0 ml water)                                                                              for labelling                                                                          10 min.                                                                            5 h   8 h                                          __________________________________________________________________________    Comparison product I                                                          0.8 mg                                                                            tin (II) flouride                                                                      5.4-6.1 GBq                                                                            0    14.3  .sup. --.sup.1                               without stabilizer                                                                         (146-165 mCi)                                                    Example 1                                                                     0.8 mg                                                                            tin (II) flouride                                                                         "     0    0     --                                           0.1 mg                                                                            compound A,.sup.2                                                             dipotassium salt                                                          Example 2                                                                     0.8 mg                                                                            tin (II) fluoride                                                                         "     0     3.8  --                                           0.1 mg                                                                            2,5-dihydroxy-                                                                phenylacetic acid                                                         Example 3                                                                     0.8 mg                                                                            tin (II) fluoride                                                                      (a) 6.8-7.9 GBq                                                                        0    0     --                                           0.2 mg                                                                            compound A,                                                                            (185-210 mCi)                                                        dipotassium salt                                                                       (b) 10.7-11.4 GBq                                                                      0    0     4.5                                                       (290-310 mCi)                                                                 (c)  "   0    0     0                                            Comparison product II                                                         1.2 mg                                                                            tin (II) fluoride                                                                      (a) 5.4-6.1 GBq                                                                        0     8-10 --                                               (50% more                                                                              (146-165 mCi)                                                        reducing agent)                                                                        (b) 10.7-11.4 GBq                                                                      0    19-20 30-31                                        without stabilizer                                                                         (290-310 mCi)                                                    __________________________________________________________________________     .sup.1 not determined                                                         .sup.2 2,5dihydroxybenzene-1,4-disulphonic acid                          

It is evident that, in the absence of a stabilizer, free pertechnetateis detectable (14.3%) in the solution after only 5 hours, and that evenincreasing the content of tin(II) ions is unable to stabilize thesolution (see comparison product I and comparison product II).

The concentration which suffices for stabilization is generally about0.1 to 6 μM of the compounds of the formula (I); a concentration of 0.5to 4 μM is usually preferred.

In the extremely low concentration mentioned, these compounds in factprove to be distinctly superior, in respect of their stabilizing action,to the complexing agents hitherto used, as is evident in Table 4 fromthe content of free pertechnetate 8 hours after labeling. The amount ofactivity used for labeling in each case was 10.7-11.1 GBq (290-300 mCi),the amount of methylenediphosphonic acid was 20 mg in each case, andthat of tin(II) fluoride was 0.8 mg in each case.

                  TABLE 4                                                         ______________________________________                                        Comparison of the action of various stabilizers                               Content of the   % content of free pertechnetate                              ampul (besides   Determination by                                             20 mg MDP and    HVE         TLRC                                             0.8 mg SnF.sub.2 in 1 ml water)                                                                10 min  8 h     10 min                                                                              8 h                                    ______________________________________                                        Example 3                                                                     0.6 μM                                                                            compound A,.sup.1                                                                           0       0-2   0     0-1                                         dipotassium salt                                                       Comparison product                                                            III                                                                           0.6 μM                                                                            4-aminobenzoic acid                                                                         0       2-9   0     0-2                                  IV                                                                            3.6 μM                                                                            4-hydroxy-                                                                    benzoic acid  0        6-15 0     3-5                                  3.6 μM                                                                            2,5-dihydroxy-                                                                benzoic acid  0       14-15 0     9-12                                        (gentisic acid)                                                        ______________________________________                                         .sup.1 2,5dihydroxybenzene-1,4-disulphonic acid?                         

Similar results in respect of the stability of the injection solutionsare obtained when other compounds are used as organ-specific ortissue-specific carrier in place of the methylenediphosphonic acid.Examples of these which may be mentioned are, for bone scintigraphy,water-soluble phosphates, polyphosphates and pyrophosphates and, inparticular, organic phosphonic acid derivatives such as, inter alia,those listed in U.S. Pat. No. 4,229,427; for static and functionalkidney investigation, for example diethylenetriaminepentaacetic acid,dimercaptosuccinic acid or a glucoheptonate; as hepatobiliary carriersthose of the nitrilotriacetic acid monoanilide series such as themono(2,6-dimethyl, 2,4,6-trimethyl, 2,6-diethyl, 2,6-diisopropyl or4-butyl)anilide and their halogen derivatives (HIDA derivatives); aswell as particulate products, for example albumin macroaggregates andmicrospheres; for scintigraphy of the reticuloendothelial systemcolloidal products, for example the micro- and nanocolloids composed ofhuman serum albumin, of sulphur or of rhenium; products composed ofproteins, for example human serum albumin or fibrinogen; productscomposed of macrocyclic compounds, for example derivatives ofmercaptoacetylglycylglycylglycine (MAG₃) and of similar tripeptides.

It ought to be emphasized in addition that the described stabilizingaction is not achieved at the expense of, for example, the organ- ortissue-specificity; the latter is in fact guaranteed to the full extent,as is evident from Table 5 in the example of ^(99m)Tc-methylenediphosphonate (MDP). Strict adherence to the organ or tissuedistribution which is specific to the particular carrier in theinjection solutions of radiodiagnostic aids stabilized according to theinvention is, of course, a principal condition for their practical use.

In order to determine the distribution of the radioactivity in theindividual organs and tissues, the injection solutions are eachadministered intravenously to groups of 5 rats, the experimental animalsare sacrificed and dissected after 2 hours, the isolated organs andtissues are combined according to their nature, and the radioactivitythereof is measured. It is expressed for the individual organs andtissues as a % of the total recovered activity±standard deviation.

                  TABLE 5                                                         ______________________________________                                        Organ distribution of .sup.99m Tc-methylenediphosphonate                      with and without stabilizer.sup.1                                                                  20 mg MDP                                                                     0.8 mg SnF.sub.2                                                                          20 mg MDP                                              20 mg MDP  0.2 mg 2.5-dihy-                                                                          0.8 mg SnF.sub.2                             Composition of                                                                          0.8 mg SnF.sub.2                                                                         droxybenzene-                                                                             0.2 mg 2.5-di-                               the solution                                                                            without    1.4-disulphonic                                                                           hydroxyphenyl-                               (1.0 ml)  stabilizer acid        acetic acid                                  (Example 3)                                                                   ______________________________________                                        Blood     0,40 ± 0,05                                                                           0,44 ± 0,08                                                                            0,46 ± 0,18                               Lungs     0,05 ± 0,01                                                                           0,06 ± 0,01                                                                            0,05 ± 0,01                               Liver     0,22 ± 0,05                                                                           0,23 ± 0,05                                                                            0,15 ± 0,04                               Spleen    0,01 ± 0,00                                                                           0,01 ± 0,00                                                                            0,01 ± 0,00                               Kidneys   0,77 ± 0,15                                                                           1,11 ± 0,60                                                                            0,60 ± 0,07                               Stomach   0,05 ± 0,01                                                                           0,06 ± 0,00                                                                            0,04 ± 0,00                               Intestinal tract                                                                        0,31 ± 0,06                                                                           0,53 ± 0,18                                                                             ,34 ± 0,07                               Bone      52,31 ± 2,04                                                                          57,25 ± 2,50                                                                           52,24 ± 1,92                              Muscle    0,90 ± 0,16                                                                           1,15 ± 0,39                                                                            0,73 ± 0,18                               Thyroid   0,00 ±  0,00                                                                          0,00 ± 0,00                                                                            0,00 ± 0,00                               Urine and 44,97 ± 2,05                                                                          39,18 ± 3,28                                                                           42,88 ± 0,58                              bladder                                                                       Total     99,99 ± 2,90                                                                          100,02 ± 4,19                                                                          97,50 ± 2,09                              ______________________________________                                         .sup.1 As % of recovered activity                                        

On wide-ranging comparison with the compounds which have hitherto beenproposed or used for the stabilization of ^(99m) Tc-labeled products,the compounds of the formula I are distinguished, at very lowconcentration, by an efficacy which is greater or the same, and, on theother hand, they make it possible to obtain scintigraphic images whosequality is not diminished by a radiation background.

Thus, the invention makes available stable ^(99m) Tc-labeled productswhich are ready for use and which are intended for use asradiodiagnostic aids and contain (a) a substance which acts as an organ-or tissue-specific carrier and labeled with the radionuclide Tc-99m, and(b) a compound of the formula (I), or a water-soluble salt thereof, inan amount which suffices to stabilize the products against oxidizingeffects.

The products according to the invention are prepared by addition to thesubstance (a) which is intended as or acts as carrier, before, during orafter the labeling thereof with the radionuclide Tc-99m, of the compounddesignated (b) above as stabilizer in a concentration which is lowerthan the concentraation of carrier.

The labeling itself is carried out by addition of a pertechnetate andexposure to a reducing agent, such as a tin(II) salt, an iron(II) saltor a chromium(II) salt, or sodium borohydride or sodium dithionite;tin(II) chloride or tin(II) fluoride is preferably used as reducingagent.

The three process variants and preferred embodiments of the inventionare described in more detail hereinafter.

I. Addition of the stabilizer before labeling

The compound chosen as stabilizer is added to a solution of the carrierand of the reducing agent; it is preferably for the solution of thethree components then to be lyophilized. The lyophilisate thus containsthe organ-specific or tissue-specific carrier, the reducing agent andthe compound intended as stabilizer; it represents a preferred agent forcarrying out the process which is defined above, and is advantageouslymarketed under vacuum in a vial.

It then suffices, in the laboratory or in the hospital, to mix thelyophilisate with the calculated amount of Tc-99m eluate from thegenerator to obtain the radiodiagnostic aid which is ready for use andis stable for several hours.

II. Addition of the stabilizer during labeling

In the second process variant, the compound intended as stabilizer ispresent in the eluate which contains the Tc-99m-pertechnetate and isintended to be used to label the carrier. An advantageous embodiment ofthe invention comprises the said compound being marketed in solid formand under vacuum in a vial which is intended to receive the eluate fromthe Tc-99m generator, the eluate being introduced into the vial, and thesolution of eluate and stabilizer being used to label the carrier, withthe assistance of a reducing agent.

However, it is also possible to introduce the stabilizer into the Tc-99mgenerator itself, before removing the eluate containing radioactivepertechnetate, and to obtain in this way an eluate which alreadycontains the stabilizer. In this embodiment, the stabilizer is likewiseadded to the carrier during labeling.

III. Addition of the stabilizer after labeling

The third process variant comprises addition of the compound chosen asstabilizer to the product which is already labeled with Tc-99m, which iscarried out by addition of an aqueous solution or of a lyophilisate ofthe said compound.

EXAMPLE 1

1.0 g of methylenediphosphonic acid (MDP) is introduced into 25 ml ofdistilled water. The pH of the acid solution is adjusted to 7.0 with 2NNaOH. Subsequently, 4.0 ml of 1% strength tin(II) fluoride solution in0.1N HCl, and 1.0 ml of a 0.5% strength solution of dipotassium2,5-dihydroxybenzene-1,4-disulphonate in distilled water are added withstirring. The solution prepared in this way is adjusted to pH 6.5 with1N HCl or 1N NaOH, and is diluted with distilled water to a final volumeof 50 ml. After sterilization by filtration through a 0.2μ sterilefilter, the filtrate is lyophilized in 1.0 ml portions in ampuls.

Ampul contents:

20 mg of MDP

0.8 mg of tin(II) fluoride

0.1 mg of dipotassium 2,5-dihydroxybenzene-1,4-disulphonate

Findings on analysis: see Table 3

EXAMPLE 2

An injection solution of the following composition is prepared as inExample 1:

Ampul contents:

20 mg of MDP

0.8 mg of tin(II) fluoride

0.1 mg of 2,5-dihydroxyphenylacetic acid

Findings on analysis: see Table 3

EXAMPLE 3

2.0 g of methylenediphosphonic acid (MDP) are introduced into 80 ml ofdistilled water. 80 mg of solid tin(II) fluoride are dissolved in theresultant acid solution (pH 1.8). Then 21 mg of solid dipotassium2,5-dihydroxy-1,4-benzenedisulphonate are added to the solution anddissolved by stirring. After the pH has been adjusted to 7.0 with 2Nsodium hydroxide solution, the solution is diluted with distilled waterto a final volume of 100 ml and then filtered through a 0.2μ sterilefilter. The filtrate is lyophilized in 1 ml portions in ampuls.

Ampul contents:

20 mg of MDP

0.8 mg of SnF₂

0.2 mg (0.6 μM) of dipotassium 2,5-dihydroxybenzene-1,4-disulphonate

Findings on analysis: see Table 3

Comparison products I and II

For comparison with Examples 1 to 3, products are prepared as in Example1 but without addition of a stabilizer and are designated comparisonproduct I and II hereinafter.

    ______________________________________                                                           I     II                                                   ______________________________________                                        Ampul contents:                                                                              MDP       20 mg   20 mg                                                       SnF.sub.2 0.8 mg  1.2 mg                                       ______________________________________                                    

Comparison products III, IV and V

For comparison with Example 3, products are prepared as in Example 1 butcontaining known stabilizers. The ampul contents (in 1.0 ml) are statedbelow; the findings on analysis are to be found in Table 4.

    ______________________________________                                        III          IV           V                                                   ______________________________________                                        20 mg of MDP 20 mg of MDP 20 mg of MDP                                        0.8 mg of SnF.sub.2                                                                        0.8 mg of SnF.sub.2                                                                        0.8 mg of SnF.sub.2                                 0.08 mg of 4-amino-                                                                        0.5 mg of 4- 0.55 mg of 2,5-                                     benzoic acid hydroxybenzoic                                                                             dihydroxybenzoic                                    (0.6 μM)  acid         acid (gentisic acid)                                             (3.6 μM)  (3.6 μM)                                         ______________________________________                                    

EXAMPLE 4

5 ml of freshly eluted ^(99m) Tc eluate with an activity of 17.17 GBq(464 mCi) are added to 0.2 ml of a 0.1% strength solution of thedipotassium salt of 2,5-dihydroxybenzene-1,4-disulphonic acid (compoundA) in water.

The peroxide content in the ^(99m) Tc eluate prepared in this way isdetermined semiquantitatively using Merckoquant test strips for peroxidetests (Merck Cat. No. 10011). The determinations are carried out aftervarious times have elapsed following treatment of the Tc-99m eluate withthe said disulphonic acid.

    ______________________________________                                        Time elapsed 10 min      5 h     8 h                                          ______________________________________                                        Peroxide content                                                                           0 ppm       0 ppm   0 ppm                                        ______________________________________                                    

EXAMPLE 5

The ^(99m) Tc eluate from Example 4 which has been treated with thedipotassium salt of 2,5-dihydroxybenzene-1,4-disulphonic acid (compoundA) is used for labeling comparison product I--composed of 20 mg of MDPand 0.8 mg of tin(II) fluoride in 1.0 ml. The content of freepertechnetate in the labeled MDP solutions is determined by thin-layerradiochromatography on Whatman paper 31 ET using acetone as mobilephase, and is expressed as a % of the activity used for labeling. Theresults are to be found in Table 6.

                  TABLE 6                                                         ______________________________________                                        Content of free pertechnetate as % of the labeling                            activity                                                                      Stabilizer                                                                             0.064 mg of compound A                                                                        0.128 mg of compound A                               ______________________________________                                        Activity of                                                                            5.437 GBq       10.7 GBq                                             the .sup.99m Tc                                                                        (147 mCi)       (289 mCi)                                            eluate                                                                        Time elapsed                                                                  after labeling                                                                10 min   0%              0%                                                    5 h     0%              0%                                                    8 h     6.6%            2.4%                                                 ______________________________________                                    

2.0 g of methylenediphosphonic acid (MDP) are dissolved in 80 ml ofdistilled water. Under a nitrogen atmosphere, 80 mg of solid tin(II)fluoride are added to the MDP solution. After the pH has been adjustedto 5.0 with 2N NaOH, 82 mg of 2,5-dihydroxybenzenesulphonic acid aredissolved therein. The solution is adjusted to a pH of 7.0 by furtheraddition of 2N NaOH, and is diluted with distilled water to a finalvolume of 100 ml. The solution is filtered through a 0.2μ sterilefilter, and the filtrate is lyophilized in 1 ml portions in ampuls.

Ampul contents:

20.0 mg MDP

0.8 mg tin(II) fluoride

0.82 mg (3.6 μM) 2,5-dihydroxybenzenesulphonic acid

Findings on analysis:

radiochromatography: see Table 7

organ distribution: see Table 8

EXAMPLE 7

A product of the following composition is prepared as in Example 6.

Ampul contents:

20.0 mg of MDP

0.8 mg of tin(II) fluoride

0.6 mg (3.6 μM) of 2,5-dihydroxyphenylacetic acid

Findings on analysis:

radiochromatography: see Table 7

organ distribution: see Table 8

EXAMPLE 8

A product of the following composition is prepared as in Example 6.

Ampul contents:

20.0 mg of MDP

0.8 mg of tin(II) fluoride

0.81 mg (3.6 μM) of 2,5-dihydroxy-4-carboxymethylphenylacetic acid

Findings on analysis:

radiochromatography: see Table 7

organ distribution: see Table 8

                  TABLE 7                                                         ______________________________________                                        Content of free pertechnetate as % of the labeling                            activity                                                                      Labeling   Example 6   Example 7 Example 8                                    activity   12,000 MBq  11,000 MBq                                                                              11,000 MBq                                   (per ampul)                                                                              (324 mCi)   (297 mCi) (297 mCi)                                    ______________________________________                                        HVE finding.sup.1                                                             10 min     0           0         0-1                                          5 h        0           0                                                      8 h        0-1         0-1       0-1                                           RC finding.sup.2                                                             10 min     0           0         0                                            5 h        0           0                                                      8 h        0-1         014 1     0-1                                          ______________________________________                                         .sup.1 By highvoltage radioelectrophoresis on Whatman paper 1 in acetate      buffer (0.04 M; pH 6.5; 30 min at 2,000 V).                                   .sup.2 By radiochromatography on Gelman ITLCSG in acetone.               

                  TABLE 8                                                         ______________________________________                                        Organ distribution of the .sup.99m Tc-methylenediphosphonate.sup.1            (rats, n = 5, 2 h after i.v. administration)                                  Labelling                                                                             Example 6    Example 7  Example 8                                     activity                                                                              12,000 MBq   11,000 MBq 11,000 MBq                                    (per ampul)                                                                           (324 mCi)    (297 mCi)  (297 mCi)                                     ______________________________________                                        Blood   0.47 ± 0.16                                                                             0.58 ± 0.06                                                                           0.62 ± 0.22                                Lungs   0.06 ± 0.01                                                                             0.05 ± 0.03                                                                           0.08 ± 0.03                                Liver   0.21 ± 0.07                                                                             0.29 ± 0.05                                                                           0.27 ± 0.08                                Spleen  0.02 ± 0.00                                                                             0.02 ± 0.00                                                                           0.02 ± 0.00                                Kidneys 0.68 ± 0.14                                                                             1.31 ± 0.34                                                                           0.81 ± 0.41                                Stomach 0.08 ± 0.03                                                                             0.11 ± 0.02                                                                           0.25 ± 0.04                                Intestinal                                                                    tract   0.45 ± 0.09                                                                             0.43 ± 0.05                                                                           0.51 ± 0.29                                Bone    41.80 ± 4.91                                                                            53.54 ± 7.95                                                                          46.07 ± 0.48                               Muscle  0.96 ± 0.25                                                                             1.16 ± 0.13                                                                           1.00 ± 0.29                                Thyroid 0.00 ± 0.00                                                                             0.00 ± 0.00                                                                           0.01 ± 0.00                                Urine   54.18 ± 7.64                                                                            38.67 ± 4.83                                                                          45.37 ± 1.32                               Total   98.91        96.16      95.01                                         ______________________________________                                         .sup.1 Mean as % of the labeling activity used                           

We claim:
 1. A process for the preparation of a stable product which islabeled with the radionuclide Tc-99m and is used as a radiodiagnosticaid, which process comprises adding to a substance which is utilized asan organ-specific or tissue-specific carrier, before, during or afterthe labeling thereof using a pertechnetate and a reducing agent, astabilizer of the formula: ##STR3## in which R denotes hydrogen, and R'denotes a sulpho- or carboxymethyl group, or R and R' each denote asulpho- or a carboxymethyl group, or of a water-soluble salt thereof, ina concentration which is less than that of the carrier.
 2. An agent forcarrying out the process as claimed in claim 1, which is in the form ofa composition of the organ-specific or tissue specific carrier, thereducing agent and the stabilizer.
 3. An agent for carrying out theprocess as claimed in claim 1, which is composed of the stabilizer insolid form and under vacuum in a vial intended to receive an eluate froma Tc-99m generator.
 4. An agent for carrying out the process as claimedin claim 1, which is in the form of a composition of the stabilizer andan eluate from a Tc-99m generator.
 5. An agent for carrying out theprocess as claimed in claim 1, wherein the stabilizer is included in aTc-99m generator itself before removing the eluate which containsradioactive pertechnetate.
 6. An agent for carrying out the process asclaimed in claim 1, which is composed of the stabilizer in the form ofan aqueous solution or of a lyophilisate, intended for addition to theradioactively labeled product.
 7. The process as claimed in claim 1,wherein a tin(II) salt, an iron(II) salt or a chromium(II) salt, sodiumborohydride or sodium dithionite is used as the reducing agent.
 8. Theprocess as claimed in claim 7, wherein the tin(II) chloride or tin(II)fluoride is used as the reducing agent.
 9. An agent for carryingout theprocess as claimed in claim 1, which is in the form of a composition ofthe reducing agent and the stabilizer.
 10. An agent as claimed in claim9, which is in the form of a lyophilisate of the composition.
 11. Anagent as claimed in claim 10, wherein the lyophilisate of thecomposition is present in a vial under vacuum.